Doublecortin expression in the normal and epileptic adult human brain

Abstract

Mesial temporal lobe epilepsy (MTLE) is a neurological disorder associated with spontaneous recurrent complex partial seizures and hippocampal sclerosis. Although increased hippocampal neurogenesis has been reported in animal models of MTLE, increased neurogenesis has not been reported in the hippocampus of adult human MTLE cases. Here we showed that cells expressing doublecortin (Dcx), a microtubule-associated protein expressed in migrating neuroblasts, were present in the hippocampus and temporal cortex of the normal and MTLE adult human brain. In particular, increased numbers of Dcx-positive cells were observed in the epileptic compared with the normal temporal cortex. Importantly, 56% of Dcx-expressing cells in the epileptic temporal cortex coexpressed both the proliferative cell marker, proliferating cell nuclear antigen and early neuronal marker, TuJ1, suggesting that they may be newly generated neurons. A subpopulation of Dcx-positive cells in the epileptic temporal cortex also coexpressed the mature neuronal marker, NeuN, suggesting that epilepsy may promote the generation of new neurons in the temporal cortex. This study has identified, for the first time, a novel population of Dcx-positive cells in the adult human temporal cortex that can be upregulated by epilepsy and thus, raises the possibility that these cells may have functional significance in the pathophysiology of epilepsy.

Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain

“…Dcx, a microtubule-associated protein, which plays an important role in neuronal migration [26], is expressed by virtually all neuroblasts and immature neurons. A recent study reported the existence of Dcx+/GFAP+ mature astrocytes in the adult human cortex [27]; however, these results may depend on the type of antibody used [24]. In the present study, we clearly observed a population of Dcx+ cells in the ventral SVZ and throughout the RMS using Figure S1), the majority of Dcx+ cells in the SVZ and RMS expressed PSA-NCAM and vice versa ( Figure 1).…”

“…Previous studies have clearly shown that there is a novel population of Dcx+ cells in the adult human temporal cortex [24]. Moreover, a fixation delay of up to 12 h has no significant difference in the pattern of Dcx immunoreactivity and the number of Dcx+ cells in the brain section [24].…”

“…Previous studies have clearly shown that there is a novel population of Dcx+ cells in the adult human temporal cortex [24]. Moreover, a fixation delay of up to 12 h has no significant difference in the pattern of Dcx immunoreactivity and the number of Dcx+ cells in the brain section [24]. Consistent with this report, using both goat and rabbit polyclonal Dcx antibodies, we observed many Dcx+ cells in layer II of the inferior temporal gyrus of the adult human brain (Supplementary information, Figure S2A-S2C).…”

“…While Dcx has been used in numerous studies as a hallmark for adult neurogenesis, the mere expression of Dcx in a small number of dispersed cells does not warrant the assumption that they are recently generated or migrating neuroblasts. Indeed, many species have Dcx+ cells in the adult brain, and these Dcx+ cells may be generated embryonically (Supplementary information, Figure S2) [24,29,30]. If Dcx+ cells in the adult human SVZ and RMS are bona fide young migrating neuroblasts, there should be at least a small number of Dcx+ cells capable of proliferating in vivo, which is typical of many neuroblasts in the adult rodent and monkey brain ( Figure 1O-1S') [9,10,28,31].…”

Compensatory Neurogenesis in the Injured Adult Brain

“…In contrast, following seizure activity BrdU+ cells were found extensively in the dentate hilus and/or dentate molecular layer of the hippocampus, indicating aberrant migration of dividing cells in response to seizure-induced cell loss (Parent, et al, 1997, Scharfman, et al, 2000, Scharfman, et al, 2002, Parent, et al, 2006. Similarly, displaced granule cells have been observed in hippocampal tissues obtained from patients with TLE (Houser, 1990, Thom, et al, 2002, Liu, et al, 2008. This suggests that acute seizure-induced dentate gyrus neurogenesis promotes aberrant circuitry development, which likely contributes to the evolution of initial seizure-induced hippocampal injury into chronic epilepsy (Kuruba, et al, 2009).…”